Abstract
The immune system homeostasis relies on a tight equilibrium of interconnected stimulatory and inhibitory signals. Disruption of this balance is characteristic of autoimmune diseases such as systemic lupus erythematosus (SLE). Aside from activating the classical complement pathway and enhancing pathogens and apoptotic cells phagocytosis, C1q has been recently shown to play an important role in immune modulation and tolerance by interacting with several inhibitory and stimulatory immune receptors. Due to its functional organization into collagen-like (CLR) and globular (GR) regions and its multimeric nature, C1q is able to interact simultaneously with several of these receptors and locally congregate pro- and anti-inflammatory signals, thus modulating the immune response. Leukocyte associated immunoglobulin-like (Ig-like) receptor 1 (LAIR-1), a ubiquitous collagen receptor expressed in many immune cell types, has been reported to interact with the CLR of C1q. In this study, we provide new insights into the molecular and structural determinants underlying C1q/LAIR-1 interaction. Recombinant LAIR-1 extracellular Ig-like domain was produced and tested for its interaction with C1q. A molecular dissection of C1q combined with competition assays reveals that LAIR-1 interacts with C1q’s CLR through a binding site close but different from the one of its associated C1r2s2 proteases tetramer. On the other side, we identified LAIR-1 residues involved in C1q interaction by site-directed mutational analysis. All together, these results lead to propose a possible model for C1q interaction with LAIR-1 and will contribute to the fundamental understanding of C1q-mediated immune tolerance.
Highlights
The ability of the immune system to provide an efficient response against pathogens without hyper reacting against host tissues relies on a tight balance between pro- and anti-inflammatory signals
LAIR-1 Ig-like domain produced in E. coli or HEK293F cells showed similar levels of interaction with C1q (Figure S1) but with slight differences in the binding curves possibly accounting for posttranslational modifications
We investigated the molecular basis of C1q interaction with LAIR-1, an inhibitory immune receptor present on various immune cells
Summary
The ability of the immune system to provide an efficient response against pathogens without hyper reacting against host tissues relies on a tight balance between pro- and anti-inflammatory signals. Assembled in six heterotrimers maintained by both noncovalent and covalent interactions, these chains are composed of a short N-terminal part containing interchain disulfide bonds (between A-B and C-C), followed by a collagen-like region (CLR) containing the characteristic repeating G-X-Y triplets (X being any amino acid and Y a proline or hydroxyproline residue) and a C-terminal globular region (GR) [3] This complex assembly leads to the formation of a 460 kDa C1q protein with a “bouquet-like” structure, where six C-terminal globular domains are connected via six collagen stems gathered in an N-terminal fiber bundle [4,5]. The collagen-like regions of C1q are engaged in immune response effector mechanisms through their interaction with a tetramer of complement C1r and C1s proteases (C1r2s2) or receptors on immune cells surface [8,9]
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